Reviews and feature article
Cytokine release syndrome and neurotoxicity following CAR T-cell therapy for hematologic malignancies

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Chimeric antigen receptor T cells are a new and exciting immunotherapeutic approach to managing cancer, with impressive efficacy but potentially life-threatening inflammatory toxicities such as cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS). Patients with severe CRS may develop capillary leak syndrome and disseminated intravascular coagulation, with a cytokine signature similar to that of macrophage activation syndrome/hemophagocytic lymphohistiocytosis. Moderate-to-severe CRS is managed with the IL-6 receptor antagonist tocilizumab with or without corticosteroids, with questions remaining regarding the optimal management of nonresponders. ICANS is an inflammatory neurotoxicity typically occurring after CRS and characterized by impaired blood-brain barrier integrity. Symptoms of encephalopathy range from mild confusion and aphasia to somnolence, obtundation, and in some cases seizures and cerebral edema. ICANS is currently managed with corticosteroids; however, the optimal dose and duration remain to be determined. Little information is available to guide the management of patients with steroid-refractory ICANS. Numerous cytokine-targeted therapies have been proposed to manage these inflammatory toxicities, but few clinical data are available. Management of inflammatory toxicities of chimeric antigen receptor T cells often requires multidisciplinary management and intensive care, during which allergists and immunologists may encounter patients with these unique toxicities.

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Background information on CAR T

CAR T are typically manufactured from autologous T cells collected via leukapheresis. In most cases, T cells are infected with a viral vector (lentivirus or retrovirus) containing the CAR DNA sequences: a single chain variable fragment, a costimulatory molecule (4-1BB or CD28), and a signal transduction molecule (CD3ζ). The sequences integrate into the T-cell genome, ultimately resulting in extracellular membrane CAR expression, which is able bind target antigen independent of HLA molecules.

Cytokine release syndrome—clinical presentation

CRS reflects antigen-nonspecific toxicity characterized by supraphysiologic immune activation following activation and expansion of CAR T binding their cognate antigen.17, 18, 19 The median onset of CRS is 2 to 3 days following infusion—usually with mild symptoms that progress gradually over hours to days. The majority of CRS cases begin within 14 days of infusion and last 7 to 8 days.13,14,16 Fever is almost always the initial sign, sometimes reaching 105°F (40.5°C) or even higher. Other

Pathogenesis of CRS

The cytokine profile of CRS is the result of activation of numerous immune cells rather than a binary interaction between CD19+ cells and CAR T. IL-6 released by activated macrophages and monocytes appears to be the primary driver of CRS,30 with higher levels observed in severe CRS.24,25 IL-1 is released from activated macrophages and monocytes, stimulating release of IL-6 and induction of nitric oxide synthetase.31,32 Serum elevations of IL-2, TNF-ɑ, IFN-ɣ, IL-8, IL-10, monocyte

Grading of CRS

In early CAR T trials it was realized that grading CRS by using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0, was not practical. For example, Common Terminology Criteria for Adverse Events grading considered the need for infusion interruption, which cannot apply to cellular therapies.40 Clinical trials with tisa-cel used the Penn scale for grading CRS,41,42 whereas trials with axi-cel used the Lee scale,17 complicating toxicity comparisons between

CRS incidence and risk factors

The incidence of CRS varies between CAR T products and by malignant disease. Following tisa-cel administration, CRS is generally less common and less severe in non-Hodgkin lymphoma than in ALL, perhaps related to burden and location of disease. All-grade and severe CRS appear more common with CAR T–containing CD28 costimulatory domains (axi-cel) than with 4-1BB costimulatory domains (tisa-cel). Although direct comparisons are challenging because of the use of different CRS grading systems and

Treatment of CRS

Many cases of CRS are self-limiting and require only symptomatic management. CAR T associated with a gradual onset of CRS symptoms enables outpatient administration, with inpatient admission necessary only if progressive CRS symptoms occur. CAR T with a more rapid onset of severe CRS may be better suited for inpatient administration, as closer observation and early intervention may be necessary. Fever is managed with acetaminophen in addition to nonpharmacologic interventions such as ice baths

Immune effector cell–associated neurotoxicity syndrome

The second most significant and potentially life-threatening CAR T adverse event is ICANS. ICANS typically occurs following peak CRS severity, with symptoms starting 4 to 5 days following CAR T infusion and lasting 5 to 10 days. Rarely, ICANS can occur without antecedent CRS, but it is generally mild in such cases. Patients can present with a multitude of symptoms, including expressive aphasia, impaired attention, confusion, tremor, obtundation, and even seizures.34, 35, 36,62 Fatal cerebral

Conclusion

The FDA approval of CAR T therapies marked a new age in cancer care, where genetic manipulation of autologous T cells results in an antigen-specific T-cell immunity against cancer cells. CAR T are likely curing some patients and extending survival for many other patients whose treatment options would be otherwise limited. Such success comes with challenges in the form of CRS and ICANS, which are potentially life-threatening inflammatory toxicities that are just beginning to be understood.

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    Disclosure of potential conflict of interest: C. W. Freyer has received speaker’s bureau and advisory board compensation from Astellas and advisory board compensation from Incyte. D. Porter receives patent and royalty fees from Novartis and honoraria for advisory board participation from Novartis, Kite, Janssen, and Incyte; his spouse receives salary, stock/options, and employment compensation from Genentech.

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